Method for the synthesis of anthrapyrazolones

Abstract

This invention relates to compounds, including 5-chloro-2-[2-[[(4-methylphenyl)sulfonyl]oxy]ethyl]-7-[2,4,6-trimethylphenyl)methoxy]anthra[1,9-cd]pyrazol-6(2H)-one and analogs thereof, which are useful as intermediates for the synthesis of anthrapyrazolone anticancer agents, including losoxantrone. This invention also relates to methods for the synthesis of anthrapyrazolone anticancer agents, including losoxantrone.

What is claimed is: 
     
       1. A process for preparing a compound of formula (V): ##STR21## or a pharmaceutically acceptable salt form thereof, wherein: x is selected from: (a) F, Cl, Br, I,   (b) methanesulfonyloxy,   (c) toluenesulfonyloxy,   (d) trifluoromethanesulfonyloxy, or   (e) --OH;   R 1  is selected from: (a) benzyl substituted with 0-3 R 5  ;   (b) naphthylmethyl substituted with 0-3 R 5  ;   (c) anthrylmethyl substituted with 0-3 R 5  ; or   (d) C 1  -C 4  alkyl; or   (e) H;     R 5  is independently selected from: C 1  -C 4  alkyl, halogen, OR 6 , NO 2  ; and   R 6  is independently selected from: H, C 1  -C 8  alkyl, C 2  -C 6  alkenyl, C 3  -C 8  cycloalkyl, C 4  -C 8  cycloalkylmethyl, C 6  -C 10  aryl, or C 7  -C 11  arylalkyl; comprising the steps of:     (1) reacting a compound of formula (IV): ##STR22## wherein: R 1  and X are as defined above; with 2-hydroxyethylhydrazine, in a suitable solvent, in the presence of a base, to form a mixture of regioisomers of formula (II) and formula (III) in which the ratio of (II) to (III) is about 4 to 1: ##STR23## wherein R 1  and X are as defined above; (2) reacting the mixture of regioisomers (II) and (III) with ClSO 2  R 2 , wherein:   R 2  is selected from: (a) C v  F 2v+1  where v is 1 to 4, or   (b) phenyl or phenyl optionally substituted with from 1 to 3 of the groups selected from Cl, F, Br, NO 2  or CH 3  ;     said reaction being carried out in a suitable solvent, in the presence of a suitable base, followed by precipitation with an alcohol or a mixture of methylene chloride and methanol to provide a single isomer of formula (I): ##STR24## wherein Y is --OSO 2  R 2  and R 1  and X are as defined above; (3) reacting the compound of formula (I) with ethanolamine in a suitable solvent in the presence of a suitable base, to form a compound of formula (V): ##STR25## wherein R 1  and X are as defined above.     
     
     
       2. A process of claim 1 wherein X is Cl, Br or I. 
     
     
       3. A process of claim 2 wherein X is Cl and Y is toluensulfonyloxy. 
     
     
       4. A process of claim 3 in which, in step (2), the base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and the reaction is carried out at a temperature ranging from about -10° C. to 10° C., for about 2 to 7 hours. 
     
     
       5. A process of claim 3 in which, in step (2), the base is pyridine and the reaction is carried out at a temperature ranging from about -10° C. to 20° C., for about 24 to 60 hours. 
     
     
       6. A process of claim 4 in which, in step (2), the precipitation solvent for generating the single isomer of formula (I) is methylene chloride and methanol. 
     
     
       7. A process of claim 5 in which, in step (2), the precipitation solvent for generating the single isomer of formula (I) is methylene chloride and methanol.